Diabetes Drug Increases Bladder Cancer, Study Shows

With commentary by lead study author Laurent Azoulay, PhD, associate professor, centre for clinical epidemiology, at Jewish General Hospital, in Montreal.

For years, a drug used to treat diabetes has been linked to an increased risk of bladder cancer, but the research to support a strong association had been lacking. Now a new study reveals strong evidence that pioglitazone does in fact increase the risk of bladder cancer, and that the increased risk can occur as quickly as about 22 months on the drug.

Warnings from the U.S. Food and Drug Administration about the risk of bladder cancer from pioglitazone were issued in 2011. The FDA warned that the use of the medication pioglitazone (Actos, Oseni, Duetact) for more than one year may be associated with an increased risk of bladder cancer, and advised those with bladder cancer not to take it. But the agency stopped short of recommending that others avoid it, even those with increased risk of the cancer. The drug remains on the market, and some of the drugs containing pioglitazone have been approved since the 2011 warning.

Researchers from Canada set out to conduct a study that avoided some of the weaknesses of past research, such as past use of medications or existing bladder cancer in subjects. They conducted a large, population-based study of more than 145,800 patients from the UK, and compared the use of pioglitazone with rosiglitazone (Avandia), which is in the same class of drugs called thiazolidinediones, as well as other diabetes drugs.

The study, published in The BMJ, included patients who were given diabetes drugs for the first time between 2000 (the year pioglitazone and rosiglitazone entered the UK market) and 2013. Patients were followed by a mean of 4.7 years. The authors excluded all patients with a diagnosis of bladder cancer and created a one-year lag time to make sure that patients did not have bladder cancer that hadn’t yet been diagnosed.

Compared with taking no thiazolidinedione, the use of pioglitazone was associated with a 63 percent increased risk of bladder cancer. The risk increased with higher doses and length of time on the drug. In contrast, the use of rosiglitazone was not associated with an increased risk of bladder cancer in any analysis.

When pioglitazone was compared to rosiglitazone head to head, pioglitazone was associated with a 48 percent increased risk of bladder cancer compared to rosiglitazone.

“We believe that our findings are quite compelling,” says Laurent Azoulay, PhD, associate professor, centre for clinical epidemiology, at Jewish General Hospital, in Montreal. “Given their similarities, any bias observed with pioglitazone would have also been expected with rosiglitazone. The fact that rosiglitazone was not associated with bladder cancer in any of our analyses provides some reassurance on the pioglitazone findings,” he says.

There’s a slight difference between the two drugs and the receptors they activate. The type that pioglitazone activates has been shown to increase the expression of carcinogenic biomarkers in the bladder. But the authors stress that additional studies are needed to better understand the mechanisms.

The authors stress that, in absolute terms, the risk of bladder cancer remains low. According to the American Cancer Society, men have a 1 in 26 chance of developing bladder cancer, while women have a 1 in 88 chance.

Azoulay suggests that doctors and patients should be aware of this association when weighing the overall risks and benefits of this therapy. “Certainly patients with bladder cancer or other bladder conditions should not use the drug, but ultimately the decision to prescribe this drug will lie with the treating physician,” says Azoulay.

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